Alopecia which is the partial or complete loss of hair may result from genetic factors, aging, antineoplastic chemotherapy or other causes. Noncicatricial alopecia occurs without scarring or gross atrophic changes. These types of alopecia include males pattern baldness, toxic alopecia, alopecia areata and trichotillomania. In recent years toxic alopecia which is by antineoplastic chemotherapy has become a more common problem as the use of chemotherapy for neoplastic diseases has expanded. This is one of the toxic effects that is seen frequently with alkylating agents, anti-metabolites, plant alkaloids, anti-tumor antibiotics and interferons is alopecia. This problem is particularly distressing to patients who are recovering from chemotherapy because it persists being after any period of hospitalization is required and causes many patients deep psychological difficulties.
Male pattern baldness and other types of alopecia have been resistant to treatment and at the present time, minoxidil is the only recognized therapy for male pattern baldness.
A composition obtained from the bacteria Serratia marcescens has been used to protect against the alopecia which is associated with the use of cytosine arabinoside and doxorubicin. This composition had no effect on alopecia which was induced by cyclophosphamide.
The applicants have discovered that noncicatricial or nonscarring alopecia including the alopecia associated with the therapeutic doses of antineoplastic agents may be avoided or reduced by the prior concomitant or subsequent administration of an effective amount of an effective tellurium compound.
It is therefore a primary object of the invention to provide a method for preventing and/or treating alopecia.
It is also an object of the invention to provide a method for preventing alopecia which is induced by antineoplastic agents.
The invention comprises a method for preventing or treating nonscarring alopecia, said method comprising administering an effective amount of a tellurium compound.
The tellurium compounds for use in the invention include those of the formula: 
or
TeO2 or complexes of TeO2xe2x80x83xe2x80x83(C)
or
PhTeCl3xe2x80x83xe2x80x83(D)
or
TeX4, when X is Cl, Br or F
or
(C6H5)4P+(TeCl3(O2C2H4))xe2x80x94xe2x80x83xe2x80x83(E)
wherein Q is Te or Se; t is 1 or 0; u is 1 or 0; v is 1 or 0; R, R1, R2, R3, R4, R5, R6, R7, R8, and R9 are the same or different and are independently selected from the group consisting of hydrogen, hydroxyalkyl of 1 to 5 carbons, hydroxy, alkyl or from 1 to 5 carbon atoms, halogen, haloalkyl of 1 to 5 carbon atoms, carboxy, alkylcarbonylalkyl of 2 to 10 carbons, alkanoyloxy of 1 to 5 carbon atoms, carboxyalkyl of 1 to 5 carbons atoms, acyl, amido, cyano, amidoalkyl of 1 to 5 carbons, N-monoalkylamidoalkyl of 2 to 10 carbons, N,N-dialkylamidoalkyl of 4 to 10 carbons, cyanoalkyl of 1 to 5 carbons alkoxy of 1 to 5 carbon atoms, alkoxyalkyl of 2 to 10 carbon atoms and xe2x80x94COR10 wherein R10 is alkyl of 1 to 5 carbons; and X is halogen; while the ammonium salt is illustrated, it is understood that other pharmaceutically acceptable salts such as K+ are within the scope of the invention. The compounds with the five membered rings are preferred.
As used herein and in the appended claims, the term alkyl of 1 to 5 carbon atoms includes straight and branched chain alkyl groups such as methyl; ethyl; n-propyl; n-butyl, and the like; the term hydroxyalkyl of 1 to 5 carbon atoms includes hydroxymethyl; hydroxyethyl; hydroxy-n-butyl; the term halkoakyl of 1 to 5 carbon atoms includes chloromethyl; 2-iodoethyl; 4-bromo-n-butyl; iodoethyl; 4-bromo-n-pentyl and the like; the term alkanoyloxy of 1 to 5 carbon atoms includes acetyl, propionyl, butanoyl and the like; the term carboxyalkyl includes carboxymethyl, carboxyethyl, ethylenecarboxy and the like; the term alkylcarbonylalkyl includes methanoylmethyl, ethanoylethyl and the like; the term amidoalkyl includes xe2x80x94CH2CONH2; xe2x80x94CH2CH2CONH2; xe2x80x94CH2CH2CH2CONH2 and the like; the term cyanoalkyl includes xe2x80x94CH2CN; xe2x80x94CH2CH2CN; xe2x80x94CH2CH2CH2CN and the like; the alkoxy, of 1 to 5 carbon atoms includes methoxy, ethoxy, n-propoxy, n-pentoxy and the like; the terms halo and halogen are used to signify chloro, bromo, iodo and fluoro; the term acyl includes R16CO wherein R16 is H or alkyl of 1 to 5 carbons such as methanoyl, ethanoyl and the like; the term aryl includes phenyl, alkylphenyl and naphthyl; the term N-monoalkylamidoalkyl includes xe2x80x94CH2CH2CONHCH3, xe2x80x94CHxe2x80x942CONHCH2CH3; the term N,N-dialkylamidoalkyl includes xe2x80x94CH2CON(CH3)2; CH2CH2CON(CH2xe2x80x94CH3)2. Compounds which are based on tellurium are the presently preferred compounds of the invention. The tellurium based compounds that are preferred include those of the formula: 
wherein X is halogen. The preferred halogen species is chloro.
Other compounds which are based on tellurium and may be used in the practice of the invention include PhTeCl3, TeO2 and TeX4 (C6H5)4 P+(TeCl3(O2C2H4))xe2x80x94(Z. Naturforsh, 36, 307-312 (1981). Compounds of the following structure are also included: 
Other compounds useful for the practice of invention include: 
wherein R11, R12, R13 and R14 are independently selected from the group consisting of hydrogen, hydroxy-alkyl of 1-5 carbons atoms, hydroxy and alkyl of 1-5 carbons atoms.
Useful dihydroxy compounds for use in the preparation of compounds of structure A or B, include those of formula I wherein R, R1, R4 and R5 are as shown in the Table:
Other dihydroxy compounds for use in the preparation of compounds A and B include those of formula II wherein R, R1, R2, R3, R4 and R5 are as shown in the Table:
Other dihydroxy compounds for use in making compound of formula A and B include those of formula III wherein R, R1, R2, R3, R4 and R5 are as shown in the Table.
Additional dihydroxy compounds include those of formula IV wherein R, R1, R2, R3, R4 and R5 are as shown in the Table.
Compounds of the following formula are also included: 
herein R15, R16, R17 and R18 are independently selected from halogen, alkyl of 1-5 carbons; aryl, acyl of 1-5 carbon hydroxyalkyl of 1-5 carbons and aminoalkyl of 1-5 carbons may be made by reacting the appropriate di, tri or tetrahaloselenide or telluride with the appropriate hydroxy compound which may be of the formula: HOxe2x80x94R19; wherein R19; is alkyl of 1 to 5 carbons, haloalkyl of 1 to 5 carbons, aryl, alkylaryl, alkylamido of 1 to 5 carbons, alkylcarbonyl of 1 to 5 carbons, cyanoalkyl of 1 to 5 carbons, cyanoalkyl of 1 to 5 carbons, and an alkoxyalkyl of 2 to 10 carbons. Specific examples of R16 include methyl, ethyl, n-propyl, phenyl, tolyl, amidoethyl, cyanomethyl, methyloxymethyl and CH2CH2COOH.
These compounds are described in U.S. Pat. No. 4,761,490 which is incorporated by reference. In addition, TeCl4; TeBr4 and compounds which give in aqueous solution TeO2 prferably in the form of a complex such as for example TeO2 complex with citric acid or ethylene glycol.
The antineoplastic agents include alkylating agents such as nitrogen mustard, cyclophosphamide, melphan, and chlorambucil. The antimetabolites include purine antagonists such as 6-mercaptopurine and 6-thioguanine; pyrimidine antagonist are cytarabine, 5-fluorouracil, 5-floxuridine, and methotrexate. Plant alkaloids include vincristine, vinblastine, colchicine, etoposide and teniposide. Anti tumor antibiotics include dactinomycin, doxorubicin, daunomycin and mitomycin.
The tellurium compound may be administered by systemic administration by the intramuscular, intravenous or intraperitoneal route to mammals including humans, at doses of 0.025 to 0.5 mg/Kg of body weight every second day.
The invention also includes the treatment or prevention of alopecia by the topical administration of an effective tellurium onto to an area of the body where it is desired to cause hair to grow or to prevent the loss of hair. This aspect of the invention is applicable to the prevention of hair loss and is based on the application of an effective tellurium compound to areas of the body, ie. scalp where hair loss has been noticed. Generally, any non-toxic vehicle may be used as a carrier for the tellurium compound at an effective concentration which will induce hair growth and/or retard and/or prevent hair loss.
Examples of suitable vehicles include petrolatum, Aquaphor, Neobase, propylene glycol, glycerin and the like. These base materials are described in Remington""s Pharmaceutical Sciences 17th Ed. Mack Publishing (1985), pp. 1301-1306 which is incorporated herein by reference. Generally, from 1 mg to 2.5 mg/Kg of body weight is applied once daily to the area to be treated. A preferred method of application is based on the use of a vehicle which is a thick liquid having a concentration of 200 xcexcg of tellurium compound/0.2 ml of solution.
When the method of the invention is practiced by parental administration, it may be preferred to administer the tellurium compound by subcutaneous injection at multiple sites (e.g. one injection per sq cm) within the affected area. The doses will be 0.25 mg/Kg to 2.5 mg/Kg of body weight given once daily, or in divided doses in an appropriate vehicle such as PBS. If desired, a dose regimen based on alternate day therapy may be used.
The tellurium compound should be administered prior to the administration of any neoplastic agent for optimal results. Simultaneous or subsequent administration of the tellurium compound with the antineoplastic agent may also be utilized.
The tellurium compound may be administered orally at 2.5 mg/Kg to 7.5 mg/Kg of body weight given once daily. If desired, a dose regimen based on alternate day therapy may be used.